Abstract

Axonal
damage is a correlate for increasing disability in multiple sclerosis.
Animal models such as experimental autoimmune encephalomyelitis (EAE)
may help to develop better therapeutical neuroprotective strategies for
the human disease. Here we investigate the pattern of axonal injury in
murine myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) induced
EAE. Inflammatory infiltration, axonal densities and expression of
amyloid precursor protein (APP), neurofilaments (SMI31 and 32) as well
as expression of sodium channels were quantified in lesions, the
perilesional area and normal appearing white matter (NAWM).
Quantification of T cells and macrophages revealed a significant
reduction of inflammatory infiltration at later disease stages despite
an increase of demyelinated areas and persistent clinical disability. In
lesions, axonal density was already significantly reduced early and
throughout all investigated disease stages. A significant axonal loss
was also seen in the grey matter and at later time points in the
perilesion as well as NAWM. Numbers of axons characterized by
non-phosphorylated neurofilaments and re-distribution of sodium channels
1.2 and 1.6 increased over the course of MOG-EAE whilst APP positive
axons peaked at the maximum of disease. Finally, double-labeling
experiments revealed a strong colocalization of sodium channels with
APP, neurofilaments and the axonal nodal protein Caspr, but not glial
and myelin markers in actively demyelinating lesions. In summary,
progressive axonal loss distant from lesions is mainly associated with
changes in neurofilament phosphorylation, re-distribution of sodium
channels and demyelination. This axonal loss is dissociated from acute
inflammatory infiltration and markedly correlates with clinical
impairment. Consequently, therapeutic intervention may be promising at
early stages of EAE focusing on inflammation, or later in disease
targeting degenerative mechanisms.

Re-expression
of a developmentally restricted potassium channel in autoimmune
demyelination: Kv1.4 is implicated in oligodendroglial proliferation.

Abstract

Mechanisms
of lesion repair in multiple sclerosis are incompletely understood. To
some degree, remyelination can occur, associated with an increase of
proliferating oligodendroglial cells. Recently, the expression of
potassium channels has been implicated in the control of oligodendrocyte
precursor cell proliferation in vitro. We investigated the expression
of Kv1.4 potassium channels in myelin oligodendrocyte
glycoprotein-induced experimental autoimmune encephalomyelitis, a model
of multiple sclerosis. Confocal microscopy revealed expression of Kv1.4
in AN2-positive oligodendrocyte precursor cells and premyelinating
oligodendrocytes in vitro but neither in mature oligodendrocytes nor in
the spinal cords of healthy adult mice. After induction of myelin
oligodendrocyte glycoprotein-induced experimental autoimmune
encephalomyelitis, Kv1.4 immunoreactivity was detected in or around
lesions already during disease onset with a peak early and a subsequent
decrease in the late phase of the disease. Kv1.4 expression was confined
to 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive
oligodendroglial cells, which were actively proliferating and ensheathed
naked axons. After a demyelinating episode, the number of Kv1.4 and
2',3'-cyclic nucleotide 3'-phosphodiesterase double-positive cells was
greatly reduced in ciliary neurotrophic factor knockout mice, a model
with impaired lesion repair. In summary, the re-expression of an
oligodendroglial potassium channel may have a functional implication on
oligodendroglial cell cycle progression, thus influencing tissue repair
in experimental autoimmune encephalomyelitis and multiple sclerosis.